The incidence of HCV-associated hepatocellular carcinoma (HCC) is rising in the United States and Europe and is likely to double or triple over the next 10 to 20 years. The overall survival rate of HCC is poor because most patients are diagnosed when the tumor is in an advanced stage. Our group has embarked on an effort to integrate genomics, transcriptomics and proteomics for the profiling of HCC. We have also utilized a proteomic approach to determine whether a distinct repertoire of autoantibodies can be detected in the sera of HCC patients and identified a diverse set of tumor antigens that induce a humoral response during the development of HCC. Our integrated DNA/RNA/Protein/Antigen approach has provided new insights into genes that are potentially important in HCC development, as well as a potential for identifying new markers for early HCC diagnosis. Our approach also provided evidence for an association between the etiology of the underlying liver disease and patterns of HCC development. We propose to integrate genomic and proteomic approaches to identify genes and proteins that are expressed distinctively between HCV-related HCCs and precursor lesions. The combination of genomic and proteomic based profiling uniquely allows delineation of global changes in expression patterns resulting from transcriptional and post-transcriptional control, posttranslational modifications and shifts in proteins between cellular compartments. It will allow the identification of changes in gone expression associated with the development of HCC, some of which may correlate with the appearance of the tumor. Testing and validation of these potential markers require high affinity probes for their detection and quantitation. For this purpose, we propose to acquire corresponding antibodies and to develop antibody-based microarrays to determine their level in sera and their utility for diagnosing HCC. The use of microarrays to this effect provides a high throughput high sensitivity and low serum volume requirement and therefore is highly advantageous. We will establish the sensitivity and specificity of the individual and combination of protein biomarkers. The identification of panels of tumor antigens that elicit a humoral response may also have utility in cancer screening and diagnosis. We propose to identify circulating antibodies to tumor antigens that will enable us to develop a blood test for HCC. [unreadable] [unreadable] [unreadable]